Mutations in the chloride channel gene CLCNKB as a cause of classic Bartter syndrome

ABSTRACT.: Inherited hypokalemic renal tubulopathies are differentiated into at least three clinical subtypes: (1) the Gitelman variant of Bartter syndrome (GS); (2) hyperprostaglandin E syndrome, the antenatal variant of Bartter syndrome (HPS/aBS); and (3) the classic Bartter syndrome (cBS). Hypokalemic metabolic alkalosis and renal salt wasting are the common characteristics of all three subtypes. Hypocalciuria and hypomagnesemia are specific clinical features of Gitelman syndrome, while HPS/aBS is a life-threatening disorder of the newborn with polyhydramnios, premature delivery, hyposthenuria, and nephrocalcinosis. The Gitelman variant is uniformly caused by mutations in the gene for the thiazide-sensitive NaCl-cotransporter NCCT (SLC12A3) of the distal tubule, while HPS/aBS is caused by mutations in the gene for either the furosemide-sensitive NaK-2Cl-cotransporter NKCC2 (SLC12A1) or the inwardly rectifying potassium channel ROMK (KCNJ1). Recently, mutations in a basolateral chloride channel CLC-Kb (CLCNKB) have been described in a subset of patients with a Bartter-like phenotype typically lacking nephrocalcinosis. In this study, the screening for CLCNKB mutations showed 20 different mutations in the affected children from 30 families. The clinical characterization revealed a highly variable phenotype ranging from episodes of severe volume depletion and hypokalemia during the neonatal period to almost asymptomatic patients diagnosed during adolescence. This study adds 16 novel mutations to the nine already described, providing further evidence that mutations in the gene for the basolateral chloride channel CLC-Kb are the molecular basis of classic Bartter syndrome. Interestingly, the phenotype elicited by CLCNKB mutations occasionally includes HPS/aBS, as well as a Gitelman-like phenotype.